CH636843A5 - METHOD FOR PRODUCING D (-) ALPHA-PHENYLGLYCIN. - Google Patents

Description

The invention relates to a process for the preparation of D (-) a-phenylglycine by splitting DLa-phenylglycine with D (+) - camphor sulfonic acid in the presence of a strong acid in a reaction vessel, the crystallized salt of D (-) a-phenylglycine being filtered off and then hydrolyzed by adding a base while precipitating the D (-) a-phenylglycine, which is then obtained by filtration, and the filtrate obtained is returned to the reaction vessel with the salt of the D (+) - camphorsulfonic acid dissolved in water , and wherein the filtrate obtained after filtering off the salt of the D (-) a-phenylglycine with L (+) a-phenylglycine therein is subjected to an alkaline racemization by means of a base and the resulting DL a-phenylglycine is likewise returned to the reaction vessel becomes.

The preparation of D (-) a-phenylglycine by splitting a racemic mixture of DL a-phenylglycine into the D and L isomers with the aid of D (+) - camphorsulfonic acid is known. The alkaline racemization of the undesired L isomer in the racemic DL

Mixture is known. The known process for the preparation of D (-) a-phenylglycine, in which the mixture is neutralized after the racemization and then filtered and the solid DLa-phenylglycine is returned to the reaction vessel and the filtrate is discarded as waste water, has the disadvantage that with salts, valuable DLa-phenylglycine and in particular D (+) - camphorsulphonic acid are thrown away into the filtrate, so that the known process is uneconomical on the one hand due to the loss of valuable starting materials which have to be supplemented each time and on the other hand causes environmental pollution.

The invention is based on the object of preventing the described intolerable disadvantages by means of suitable measures.

For this purpose, the invention teaches that H2SO4 is used as the strong acid and the L (+) a-phenylglycine is racemized without separation from the racemization mixture in the presence of the D (+) - campersulfonic acid under the influence of KOH or NaOH, that during the increased Temperature racemization water is distilled off, which is then used for the hydrolysis, that the racemization mixture is then cooled with crystallization of K2SO4 or Na2S04, the latter being obtained by filtration, and the resulting filtrate, which is the K or Na salt contains the DLa-phenylglycine and the K or Na salt of the camphorsulfonic acid dissolved in water, is returned to the reaction vessel, whereupon a further mixture to be broken down is produced by supplementing the DLa-phenylglycine and adding sulfuric acid again.

With this procedure, practically every loss of D (-) a-phenylglycine and D (+) - camphor sulfonic acid is avoided, moreover no process waste water is discarded and thus no environmental pollution is caused. The solid salts formed, such as K2SO4 when using KOH or Na2S04 when using NaOH, are removed from the racemic mixture by filtration and can be used for other purposes, e.g. in the case of K2SO4 as an artificial fertilizer in agriculture.

The process according to the invention will now be explained in more detail with the aid of the enclosed process scheme:

The starting cleavage mixture in the reaction vessel is fed in addition to DLa-phenylglycine H2SO4 in order to convert the recovered K or Na salt of D (+) - camphor sulfonic acid into the free acid, to neutralize the alkaline racemization mixture and to add the newly added DL a-phenylglycine in solution bring. KOH or NaOH and water are added to the salt of D (-) a-phenylglycine and D (+) - camphor sulfonic acid which has crystallized out after separation from the cleavage mixture, the D (-) a-phenylglycine crystallizing out and the K- or Na salt of D (+) - campfer sulfonic acid goes into solution. After the desired D (-) a-phenylglycine has been separated off, the solution of the K or Na salt of D (+) camphorsulfonic acid is returned to the reaction vessel and used again in the reaction vessel for further splitting.

The filtrate of the cleavage mixture contains the predominant proportion of D (+) - campfer sulfonic acid, L (+) a-phenylglycine and ICHSO4 or NaHS04. By adding KOH or NaOH, the pH is brought to 11 or higher, preferably to 11 to 13. The mixture is then boiled at 100 to 120 ° C. for 1.5 to 4 hours in order to racemize the L isomer in DL. At the same time, part of the water from the racemization mixture is distilled off in order not to increase the volume of the process liquid. The distilled water is used for washing the various filtered solids and for the hydrolysis of the salt of D (-) a-phenylglycine and D (+) - camphor sulfone.

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acid used. As a result of the subsequent cooling of the racemization mixture to 18 to 30 ° C., the K2SO4 or Na2SC> 4 present in the process liquid surprisingly crystallizes out practically quantitatively and can be separated off by simple filtration. The Na2SC> 4 crystals have 10 moles of water of crystallization. The liquid, which contains DLa-phenylglycine and the K or Na salt of D (+) - camphor sulfonic acid, is returned to the reaction vessel and used again in the subsequent splitting.

The process according to the invention is illustrated by the following examples:

Example I

1. Splitting (KOH)

A mixture of 1200 ml of water, 2 mol (302 g) of DLa-phenylglycine, 1.2 mol (278.5 g) of D (+) camphorsulfonic acid and 0.8 mol (78.4 g) of H2SO4 was stirred in a reaction vessel . The cleavage mixture was heated to 90-100 ° C. while stirring, the DLa-phenylglycine dissolving. The solution was then cooled to 15-30 ° C. with stirring, during which the salt of D (-) a-phenylglycine crystallized out. The crystals were filtered off and washed with a little water. Yield of salt about 300 g.

hydrolysis

The salt formed during the splitting was added to 500 ml of water with stirring. The mixture was brought to a pH of 3.5 to 6 by adding about 42 g of KOH, dissolved in 60 ml of water. The reaction mixture was then cooled and the crystallized D (-) a-phenylglycine was filtered off. The crystals were washed on the filter with a little water. The product was then dried. Yield: 118 g, content via acid / base titration 99%. Specific rotation [a] D§, = -160 °.

Racemization

The filtrate from the cleavage mixture and the washing liquid were stirred and made alkaline with about 3.22 mol (185 g) KOH to a pH above 11. For racemization, the mixture was subsequently heated at 100 to 120 ° C. for 3 hours, enough water to be distilled off that the volume decreased to about 900 ml. The mixture was then cooled to 20 ° C. with stirring. Here, K2SO4 crystallized, which was separated off by filtration. The crystals were washed with a little water that had been distilled off during the racemization. Yield K2SO4 approx. 136 g. The filtrate with a volume of about 750 ml was returned to the reaction vessel and reused in the subsequent splitting.

Example II

2nd and subsequent splitting

In the reaction vessel according to Example I, a mixture of the filtrate obtained after the hydrolysis according to Example I, which contains 0.8 mol (217 g) K salt of the D (+) - camphorsulfonic acid in water and a little D (-) a-phenylglycine contained and had a volume of approx. 1400 ml, the filtrate retained after filtering the racemization mixture from Example I, which contained 1.2 mol (181.4 g) DLa-phenylglycine, 0.4 mol (108.5 g) K- Salt of the D (+) - camphorsulfonic acid and 1.22 mol (68.4 g) KOH dissolved in water and had a total volume of about 750 ml, and a new addition of 8.8 mol (120.9 g) DLa -Phenylglycine and 4.4 mol (431.2 g) H2SO4 stirred. The cleavage mixture was heated to 90-100 ° C. with stirring, the DLa-phenylglycine going into solution. The solution was then stirred to 15 to

Cooled to 30 ° C. The salt of D (-) a-phenylglycine crystallized out. The crystals were filtered off and washed with a little water which had been distilled off during the previous racemization. Yield of salt approx. 307 g.

hydrolysis

The salt formed during the splitting was introduced with stirring into 500 ml of water which had been distilled off during the previous racemization. The mixture was adjusted to a pH of 3.5 to 6 by adding about 45 g of KOH, dissolved in 60 ml of water. The reaction mixture was cooled to 15 to 35 ° C. and the crystallized D (-) a-phenylglycine was filtered off. The crystals were washed on the filter with a little water that had been distilled during the previous racemization. The product was then dried. Yield: 121g; Acid / base titration content 99%. Specific rotation [a]% - -160 °.

Racemization

The filtrate of the cleavage mixture and the washing liquid were stirred and made alkaline with about 8 mol (449 g) KOH to a pH above 11. For racemization, the mixture was subsequently heated at 100 to 120 ° C. for 3 hours, enough water to be distilled off so that the volume decreased to approximately 950 ml. The mixture was then cooled to 20 ° C. with stirring. Here, K2SO4 crystallized, which was separated off by filtration. The crystals were washed with a little water that had been distilled off during the racemization. Yield K2SO4 after drying approx. 766 g.

The filtrate of approx. 750 ml was returned to the reaction vessel and reused in the subsequent splitting.

Example III

1. Splitting

A mixture of 1200 ml of water, 2 mol (302 g) of DLa-phenylglycine, 1.2 mol (278.5 g) of D (+) camphorsulfonic acid and 0.8 mol (78.4 g) of H2SO4 was stirred in a reaction vessel . The cleavage mixture was heated to 90-100 ° C. while stirring, the DLa-phenylglycine dissolving. The solution was then cooled to 15 ° to 30 ° C. with stirring, during which the salt of D (-) a-phenylglycine crystallized out. The crystals were filtered off and washed with a little water. Yield of salt about 300 g.

hydrolysis

The salt formed during the splitting was added to 500 ml of water with stirring. The mixture was adjusted to a pH of 3.5 to 6 by adding about 31 g of NaOH dissolved in 55 ml of water. The reaction mixture was cooled and the crystallized D (-) a-phenylglycine was filtered off. The crystals were washed on the filter with a little water. The product was then dried. Yield: 118 g; Acid / base titration content 99%. Specific rotation [a] §> = -160 °.

Racemization

The filtrate of the cleavage mixture and the washing liquid were stirred and made alkaline with about 3.22 mol (129 g) NaOH to a pH above 11. For racemization, the mixture was subsequently heated at 100 to 120 ° C. for 3 hours, enough water to be distilled off so that the volume decreased to about 850 ml. The mixture was then cooled to 20 ° C. with stirring. Here, Na2S04 crystallized. IOH2O from, which is filtered off5

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was separated. The crystals were washed with a little water that had been distilled off during the racemization. Yield Na2SO ». 1OH2O approx. 259 g. The filtrate of approx. 750 ml was returned to the reaction vessel and reused in the subsequent splitting.

Example IV

2nd and subsequent splitting

In a reaction vessel, a mixture of the filtrate obtained by the hydrolysis of Example III, which contains 0.8 mol (203.2 g) Na salt of D (+) - camphorsulfonic acid in water and a little D (-) a -Phenylglycine and had a volume of about 700 ml, the filtrate retained after filtering the racemization mixture from the previous preparation, which 1.2 mol (181.4 g) DLa-phenylglycine 0.4 mol (101.6 g) Na salt of D (+) - camphorsulfonic acid and 1.22 mol (48.8 g) NaOH, dissolved in water and had a total volume of approx. 750 ml, and a new addition of 0.8 mol (120.9 g) DLa-phenylglycine and 4.4 mol (431.2 g) H2SO4 stirred. The cleavage mixture was heated to 90-100 ° C. with stirring, the DLa-phenylglycine going into solution. The solution was then cooled to 15 ° to 30 ° C. with stirring, the salt of D (-) a-phenylglycine and D (+) - camphor sulfonic acid crystallizing out. The crystals were filtered off and washed with a little water. Yield of salt approx. 307 g.

hydrolysis

The salt formed during the splitting was introduced with stirring into 500 ml of water which had been distilled off in the previous racemization. The mixture was brought to a pH of 3.5 to 6 by adding about 32 g of NaOH, dissolved in 54 ml of water. The reaction mixture was cooled to 15 to 35 ° C. and the crystallized D (-) a-phenylglycine was filtered off. The crystals were washed on the filter with a little water. The product was dried. Yield 121g; Acid / base titration content 99%. Specific rotation [a] ^ = -160 ° C.

Racemization ls The filtrate of the cleavage mixture and the washing liquid were stirred and made alkaline with about 8 mol (320 g) NaOH to a pH above 11. For racemization, the mixture was subsequently heated at 100 to 120 ° C. for 3 hours, with so much water being stilled that the volume decreased to 1500 ml. The mixture was then cooled to 18 ° C. with stirring. Here, Na2SÛ4 crystallized. IOH2O, which was separated by filtration. The crystals were washed with a little water. Yield of Na2SÛ4. IOH2O approx. 1416g. 750 ml of Fil-25 was returned to the reaction vessel and reused in the subsequent splitting.

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Claims (4)

636 843 PATENT CLAIMS 1. Process for the preparation of D (-) a-phenylglycine by splitting DLa-phenylglycine with D (+) - camphor sulfonic acid in the presence of a strong acid in a reaction vessel, the crystallized salt of D (-) a-phenylglycine being filtered off and then is hydrolyzed by adding a base to precipitate the D (-) a-phenylglycine, which is then recovered by filtration, and the filtrate obtained is returned to the reaction vessel with the salt of the D (+) - camphorsulfonic acid dissolved in water, and the filtrate obtained after filtering off the salt of the D (-) a-phenylglycine and the L (+) a-phenylglycine therein is subjected to an alkaline racemization by means of a base and the DL a-phenylglycine obtained in this way is likewise returned to the reaction vessel, characterized in that H2SO4 is used as the strong acid and the L (+) a-phenylglycine is racemized without separation from the racemization mixture in the presence of the D (+) - camphor sulfonic acid under the influence of KOH or NaOH, that during which takes place at elevated temperature Racemization Water is distilled off, which is then used for the hydrolysis, then the racemization mixture is cooled with crystallization of K2SO4 or Na2S04, the latter being obtained by filtering, and the resulting filtrate, which is the K or Na salt of the DLa Contains phenylglycine and the K or Na salt of camphor sulfonic acid dissolved in water, is returned to the reaction vessel, whereupon a further mixture to be broken down is produced by supplementing the DLa-phenylglycine and again adding sulfuric acid. 2. The method according to claim 1, characterized in that before the racemization, the pH of the mixture is adjusted to 11 to 13 by adding KOH or NaOH. 3. The method according to claim 1 or 2, characterized in that the racemization is carried out at 100 to 120 ° C for 1.5 to 4 hours. 4. The method according to any one of claims 1 to 3, characterized in that the mixture after the racemization is cooled to 18 to 30 ° C, the K2SO4 or Na2SÛ4 crystallizing out.